Domain Generalization in Computational Pathology: Survey and Guidelines

Deep learning models have exhibited exceptional effectiveness in Computational Pathology (CPath) by tackling intricate tasks across an array of histology image analysis applications. Nevertheless, the presence of out-of-distribution data (stemming from a multitude of sources such as disparate imaging devices and diverse tissue preparation methods) can cause \emph{domain shift} (DS). DS decreases the generalization of trained models to unseen datasets with slightly different data distributions, prompting the need for innovative \emph{domain generalization} (DG) solutions. Recognizing the potential of DG methods to significantly influence diagnostic and prognostic models in cancer studies and clinical practice, we present this survey along with guidelines on achieving DG in CPath. We rigorously define various DS types, systematically review and categorize existing DG approaches and resources in CPath, and provide insights into their advantages, limitations, and applicability. We also conduct thorough benchmarking experiments with 28 cutting-edge DG algorithms to address a complex DG problem. Our findings suggest that careful experiment design and CPath-specific Stain Augmentation technique can be very effective. However, there is no one-size-fits-all solution for DG in CPath. Therefore, we establish clear guidelines for detecting and managing DS depending on different scenarios. While most of the concepts, guidelines, and recommendations are given for applications in CPath, we believe that they are applicable to most medical image analysis tasks as well.

MoMA: Momentum Contrastive Learning with Multi-head Attention-based Knowledge Distillation for Histopathology Image Analysis

There is no doubt that advanced artificial intelligence models and high quality data are the keys to success in developing computational pathology tools. Although the overall volume of pathology data keeps increasing, a lack of quality data is a common issue when it comes to a specific task due to several reasons including privacy and ethical issues with patient data. In this work, we propose to exploit knowledge distillation, i.e., utilize the existing model to learn a new, target model, to overcome such issues in computational pathology. Specifically, we employ a student-teacher framework to learn a target model from a pre-trained, teacher model without direct access to source data and distill relevant knowledge via momentum contrastive learning with multi-head attention mechanism, which provides consistent and context-aware feature representations. This enables the target model to assimilate informative representations of the teacher model while seamlessly adapting to the unique nuances of the target data. The proposed method is rigorously evaluated across different scenarios where the teacher model was trained on the same, relevant, and irrelevant classification tasks with the target model. Experimental results demonstrate the accuracy and robustness of our approach in transferring knowledge to different domains and tasks, outperforming other related methods. Moreover, the results provide a guideline on the learning strategy for different types of tasks and scenarios in computational pathology. Code is available at: \url{https://github.com/trinhvg/MoMA}.

Centroid-aware feature recalibration for cancer grading in pathology images

Cancer grading is an essential task in pathology. The recent developments of artificial neural networks in computational pathology have shown that these methods hold great potential for improving the accuracy and quality of cancer diagnosis. However, the issues with the robustness and reliability of such methods have not been fully resolved yet. Herein, we propose a centroid-aware feature recalibration network that can conduct cancer grading in an accurate and robust manner. The proposed network maps an input pathology image into an embedding space and adjusts it by using centroids embedding vectors of different cancer grades via attention mechanism. Equipped with the recalibrated embedding vector, the proposed network classifiers the input pathology image into a pertinent class label, i.e., cancer grade. We evaluate the proposed network using colorectal cancer datasets that were collected under different environments. The experimental results confirm that the proposed network is able to conduct cancer grading in pathology images with high accuracy regardless of the environmental changes in the datasets.

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.

GradMix for nuclei segmentation and classification in imbalanced pathology image datasets

An automated segmentation and classification of nuclei is an essential task in digital pathology. The current deep learning-based approaches require a vast amount of annotated datasets by pathologists. However, the existing datasets are imbalanced among different types of nuclei in general, leading to a substantial performance degradation. In this paper, we propose a simple but effective data augmentation technique, termed GradMix, that is specifically designed for nuclei segmentation and classification. GradMix takes a pair of a major-class nucleus and a rare-class nucleus, creates a customized mixing mask, and combines them using the mask to generate a new rare-class nucleus. As it combines two nuclei, GradMix considers both nuclei and the neighboring environment by using the customized mixing mask. This allows us to generate realistic rare-class nuclei with varying environments. We employed two datasets to evaluate the effectiveness of GradMix. The experimental results suggest that GradMix is able to improve the performance of nuclei segmentation and classification in imbalanced pathology image datasets.

IMPaSh: A Novel Domain-shift Resistant Representation for Colorectal Cancer Tissue Classification

The appearance of histopathology images depends on tissue type, staining and digitization procedure. These vary from source to source and are the potential causes for domain-shift problems. Owing to this problem, despite the great success of deep learning models in computational pathology, a model trained on a specific domain may still perform sub-optimally when we apply them to another domain. To overcome this, we propose a new augmentation called PatchShuffling and a novel self-supervised contrastive learning framework named IMPaSh for pre-training deep learning models. Using these, we obtained a ResNet50 encoder that can extract image representation resistant to domain-shift. We compared our derived representation against those acquired based on other domain-generalization techniques by using them for the cross-domain classification of colorectal tissue images. We show that the proposed method outperforms other traditional histology domain-adaptation and state-of-the-art self-supervised learning methods. Code is available at: https://github.com/trinhvg/IMPash .

XY Network for Nuclear Segmentation in Multi-Tissue Histology Images

Nuclear segmentation within Haematoxylin & Eosin stained histology images is a fundamental prerequisite in the digital pathology work-flow, due to the ability for nuclear features to act as key diagnostic markers. The development of automated methods for nuclear segmentation enables the quantitative analysis of tens of thousands of nuclei within a whole-slide pathology image, opening up possibilities of further analysis of large-scale nuclear morphometry. However, automated nuclear segmentation is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intra-class variability such as the tumour cells. Additionally, some of the nuclei are often clustered together. To address these challenges, we present a novel convolutional neural network for automated nuclear segmentation that leverages the instance-rich information encoded within the vertical and horizontal distances of nuclear pixels to their centres of mass. These distances are then utilised to separate clustered nuclei, resulting in an accurate segmentation, particularly in areas with overlapping instances. We demonstrate state-of-the-art performance compared to other methods on four independent multi-tissue histology image datasets. Furthermore, we propose an interpretable and reliable evaluation framework that effectively quantifies nuclear segmentation performance and overcomes the limitations of existing performance measures.

Methods for Segmentation and Classification of Digital Microscopy Tissue Images

High-resolution microscopy images of tissue specimens provide detailed information about the morphology of normal and diseased tissue. Image analysis of tissue morphology can help cancer researchers develop a better understanding of cancer biology. Segmentation of nuclei and classification of tissue images are two common tasks in tissue image analysis. Development of accurate and efficient algorithms for these tasks is a challenging problem because of the complexity of tissue morphology and tumor heterogeneity. In this paper we present two computer algorithms; one designed for segmentation of nuclei and the other for classification of whole slide tissue images. The segmentation algorithm implements a multiscale deep residual aggregation network to accurately segment nuclear material and then separate clumped nuclei into individual nuclei. The classification algorithm initially carries out patch-level classification via a deep learning method, then patch-level statistical and morphological features are used as input to a random forest regression model for whole slide image classification. The segmentation and classification algorithms were evaluated in the MICCAI 2017 Digital Pathology challenge. The segmentation algorithm achieved an accuracy score of 0.78. The classification algorithm achieved an accuracy score of 0.81.

BACH: Grand Challenge on Breast Cancer Histology Images

Breast cancer is the most common invasive cancer in women, affecting more than 10% of women worldwide. Microscopic analysis of a biopsy remains one of the most important methods to diagnose the type of breast cancer. This requires specialized analysis by pathologists, in a task that i) is highly time- and cost-consuming and ii) often leads to nonconsensual results. The relevance and potential of automatic classification algorithms using hematoxylin-eosin stained histopathological images has already been demonstrated, but the reported results are still sub-optimal for clinical use. With the goal of advancing the state-of-the-art in automatic classification, the Grand Challenge on BreAst Cancer Histology images (BACH) was organized in conjunction with the 15th International Conference on Image Analysis and Recognition (ICIAR 2018). A large annotated dataset, composed of both microscopy and whole-slide images, was specifically compiled and made publicly available for the BACH challenge. Following a positive response from the scientific community, a total of 64 submissions, out of 677 registrations, effectively entered the competition. From the submitted algorithms it was possible to push forward the state-of-the-art in terms of accuracy (87%) in automatic classification of breast cancer with histopathological images. Convolutional neuronal networks were the most successful methodology in the BACH challenge. Detailed analysis of the collective results allowed the identification of remaining challenges in the field and recommendations for future developments. The BACH dataset remains publically available as to promote further improvements to the field of automatic classification in digital pathology.